title: Trypanosoma brucei brucei: a systematic screening for alternatives to the salicylhydroxamic acid-glycerol combination.
abstract: Salicylhydroxamic acid (SHAM) and glycerol, when administered together, cause destruction of bloodstream forms of Trypanosoma brucei brucei, both in vitro and in vivo, but the dose required is exceedingly high. In an attempt to improve the efficacy of this drug combination, we examined the ability of various polyols and hydroxamic acids to substitute for glycerol and SHAM, respectively. No satisfactory substitute for glycerol was found. The inhibition of the trypanosomal alpha-glycerophosphate oxidase system (GPO) by SHAM (Ki 21 microM) was uncompetitive. Only primary and secondary aromatic hydroxamates were inhibitory. Among a series of 19 benzhydroxamates, no correlation existed between their acidity or their affinity for iron and their inhibition of the GPO in a cell free preparation. The Ki's of most of the primary hydroxamates ranged from 10 to 24 microM, with the more lipophilic derivatives being slightly more active. The Ki's of secondary hydroxamates were more variable, the best having Ki's of about 10 microM. Several other classes of iron chelators were also evaluated. Tropolones were active with 3-bromo-4,5-benzotropolone being as active as SHAM. 3,4-Dihydroxybenzaldehyde (Ki 15 microM) also inhibited the GPO. On the other hand, diphenylamine and 8-hydroxyquinoline, known inhibitors of the GPO, were 30 to 50 times less active. The results suggest that a lipophilic aromatic iron-chelating agent may be useful as a substitute for SHAM in combination therapy.
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004353:Drug Evaluation, Preclinical; D005990:Glycerol / Q000494:pharmacology*; D005993:Glycerolphosphate Dehydrogenase / Q000037:antagonists & inhibitors*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D012457:Salicylamides / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014334:Tropolone / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology
chemical_list: D006877:Hydroxamic Acids; D007502:Iron Chelating Agents; D012457:Salicylamides; D014334:Tropolone; C005703:salicylhydroxamic acid; D005993:Glycerolphosphate Dehydrogenase; D005990:Glycerol